This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
Dysregulation of normal cellular signaling events has been attributed to a variety of diseases most notably cancer. Chronic myeloid leukemia (CML) is a hematological malignancy, characterized by unregulated growth of myeloid cells in the bone marrow, and their accumulation in the bloodstream. Expression of the Bcr-Abl oncogene is the primary driver in CML. Bcr-Abl is encoded on the mutant Philadelphia chromosome which arises from the translocation of chromosomes 9 and 22. This translocation involves the replacement of an autoinhibitory domain portion of the N-terminus of Abl with the Breakpoint-cluster-region (Bcr) protein. The expression of this fusion gene results in a protein product with constitutive tyrosine kinase activity.
The small molecule drug imatinib mesylate (Gleevec®) directly targets and inhibits the Abl kinase, and thus has become a frontline treatment for CML. Many patients undergoing Gleevec treatment do very well for many years, while some patients do not respond at all. Over time, some patients develop imatinib resistance such as Bcr-Abl point mutations or up-regulation of other kinases. Unfortunately, clinical signs of resistant cells repopulating the bone marrow are often not evident until CML has reached blast crisis. Second generation drugs such as nilotinib and dasatinib offer additional therapeutic options to overcome drug resistance. Assays to measure the activity of Bcr-Abl in patient cells could improve the longevity and treatment options available to CML patients through earlier detection of drug resistance. Furthermore, assays that could be used to evaluate inhibitor pharmacodynamics in preclinical animal models would benefit kinase inhibitor development by enabling more thorough characterization of drug efficacy and response.